Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine

被引:144
作者
Buzza, Marguerite S. [1 ,2 ]
Netzel-Arnett, Sarah [1 ,2 ]
Shea-Donohue, Terez [3 ]
Zhao, Aiping [3 ]
Lin, Chen-Yong [4 ]
List, Karin [5 ,6 ]
Szabo, Roman [7 ]
Fasano, Alessio [3 ]
Bugge, Thomas H. [7 ]
Antalis, Toni M. [1 ,2 ]
机构
[1] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA
[4] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA
[5] Wayne State Univ, Dept Pharmacol, Detroit, MI 48201 USA
[6] Karmanos Canc Inst, Detroit, MI 48201 USA
[7] Natl Inst Dent & Cranofacial Res, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD 20892 USA
基金
英国医学研究理事会; 美国国家卫生研究院;
关键词
claudin-2; intestinal barrier; St14; type II transmembrane serine protease; tight junction; SURFACE PROTEOLYTIC-ENZYMES; INFLAMMATORY-BOWEL-DISEASE; KINASE C-ZETA; TIGHT JUNCTIONS; CELL-LINES; EXPRESSION; ACTIVATION; CLAUDIN-2; DIFFERENTIATION; INHIBITION;
D O I
10.1073/pnas.0903923107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The intestinal epithelium serves as a major protective barrier between the mammalian host and the external environment. Here we show that the transmembrane serine protease matriptase plays a pivotol role in the formation and integrity of the intestinal epithelial barrier. St14 hypomorphic mice, which have a 100-fold reduction in intestinal matriptase mRNA levels, display a 35% reduction in intestinal transepithelial electrical resistance (TEER). Matriptase is expressed during intestinal epithelial differentiation and colocalizes with E-cadherin to apical junctional complexes (AJC) in differentiated polarized Caco-2 monolayers. Inhibition of matriptase activity using a specific peptide inhibitor or by knockdown of matriptase by siRNA disrupts the development of TEER in barrier-forming Caco-2 monolayers and increases paracellular permeability to macromolecular FITC-dextran. Loss of matriptase was associated with enhanced expression and incorporation of the permeability associated, "leaky" tight junction protein claudin-2 at intercellular junctions. Knockdown of claudin-2 enhanced the development of TEER in matriptase-silenced Caco-2 monolayers, suggesting that the reduced barrier integrity was caused, at least in part, by an inability to regulate claudin-2 expression and incorporation into junctions. We find that matriptase enhances the rate of claudin-2 protein turnover, and that this is mediated indirectly through an atypical PKC zeta-dependent signaling pathway. These results support a key role for matriptase in regulating intestinal epithelial barrier competence, and suggest an intriguing link between pericellular serine protease activity and tight junction assembly in polarized epithelia.
引用
收藏
页码:4200 / 4205
页数:6
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